Due to advances in diagnostics and treatment, the 5-year survival rate for early breast cancer has surpassed 90% in the Western world, and the number of breast cancer survivors (BCSs) is steadily increasing. Long-term BCS (ie, living beyond 5 years after diagnosis) are at increased risk of several late effects, such as increased risk of cardiovascular disease (CVD) and incidence cardiovascular (CV) risk factors (eg, obesity, hypertension, and dyslipidemia) [1,2].

Cardiotoxicity is a well-recognized adverse effect of anthracycline therapy, which has been a key component of breast cancer therapy for decades. Anthracycline treatment can induce myocardial damage [3,4] and lead to irreversible left ventricular dysfunction and heart failure [5]. Although the incidence of manifested anthracycline-induced cardiotoxicity after breast cancer treatment is approximately 2%-5% [6,7], the incidence of subclinical left ventricular dysfunction may be significantly higher [8].

Previous studies have demonstrated impaired cardiorespiratory fitness (CRF) in BCSs [9,10]. CRF is an integrative measure of global cardiopulmonary and skeletal muscle function assessed as peak oxygen consumption (VO_2peak). Reduced CRF is not only an expression of impaired physical functional capacity but is also associated with a greater risk of CVD [11,12]. Cardiac output, pulmonary function, blood oxygen carrying capacity, and peripheral arteriovenous oxygen extraction capacity are physiological determinants of CRF, also termed as limiting factors for CRF. Given the systemic effect of chemotherapy, anthracycline-induced late effects may not be limited to cardiotoxicity, but likely affects the entire cardiopulmonary-muscle axis [13]. In line with this perspective, studies have reported reduced microvessel density, impaired mitochondrial function, and reduced skeletal muscle cell size during anthracycline treatment of breast cancer [14]. To our knowledge, no study has investigated if such adverse effects are present in long-term BCS.

BCS may also face psychosocial late effects, including body image concerns, increased levels of mental distress [15], and chronic fatigue [16,17], potentially negatively affecting their work life and reducing their health-related quality of life (HRQoL) [18,19].

Aerobic exercise has shown to improve CRF in cancer survivors [20], but knowledge on the effects of aerobic exercise on limiting factors for CRF is sparse. To the best of our knowledge, there are no existing data on the effects of exercise training on cardiac morphology and function after anthracycline exposure in long-term cancer survivors.

In nononcological settings, higher levels of physical activity are associated with a dramatic reduction in CVD risk [21]. Studies evaluating such effects among cancer survivors are limited [22]. Adams et al [23] reported improved vascular function and CRF and lower low-density lipoprotein and high-sensitivity C-reactive protein after 12 weeks of supervised high intensity aerobic exercise in survivors of testicular cancer, and similar data on BCS are missing. Finally, exercise training has also been shown to improve mental distress and fatigue [24], and improve HRQoL [25,26] in patients with cancer, but research has mainly been conducted during or shortly after treatment.

The primary aim of this study is to examine the effect of aerobic exercise on CRF in anthracycline-treated long-term BCS compared to standard care. Secondary aims are to examine the effects of exercise training on limiting factors for CRF, CV risk factors, and health-related patient-reported outcomes (PROMs) compared to standard care, and to compare baseline values and effects of exercise training between BCS and similar-aged women without prior cancer. Tertiary aims are to investigate long-term effects of the intervention on CRF, CV risk factors, and health-related outcomes 24 months post intervention. We hypothesize that aerobic exercise will improve CRF.

The CAUSE (Cardiovascular Survivors Exercise) trial is conducted according to the Helsinki Declaration, and all study participants will sign informed consent before any study-related procedures. The study is approved by the Regional Committees for Medical and Health Research Ethics (2019/1318) and is preregistered on clinicaltrials.gov (NCT04307407).

The CAUSE trial is a 2-armed, phase II randomized controlled trial that compares aerobic exercise (exercise group) to standard care (control group) in BCS. A third group comprising similar-aged women with no previous cancer diagnosis is also included (noncancer reference group). The exercise group and the noncancer reference group undergoes the same aerobic exercise program. The overall study design is outlined in Figure 1.

Women who were diagnosed with breast cancer stage I-III between 2008 and 2012, and live within reasonable distance from Oslo, are identified from the Cancer Registry of Norway. An invitation with study information is sent by mail to all candidates. Thereafter, the study personnel contact the candidates by phone to screen for eligibility and provide additional information. Candidates who meet the eligibility criteria and are willing to participate are then invited to baseline assessments.

Participants for the noncancer reference group are recruited in 2 steps. First, BCS randomized to the exercise group are encouraged to invite a similar-aged friend or relative to participate in the noncancer reference group. The remaining participants in the noncancer reference group are recruited through advertisements in news media and through appropriate social media channels. Interested candidates who meet the eligibility criteria are included.

BCS are block randomized with a 1:1 allocation ratio to the exercise group or to the control group. Due to the strict eligibility criteria, no additional stratification factors are included. A random sequence of study IDs was made by a random number generator prior to inclusion of the first participant. The allocation sequence is concealed from the study personnel involved in baseline assessment until the baseline assessments are completed.

The intervention duration is 5 months. Participants in the exercise group perform 3 weekly aerobic exercise sessions aimed at increasing CRF. The exercise plan includes both continuous sessions, with low to moderate exercise intensities, as well as interval sessions performed at higher intensities. The intensity and duration of each individual session and sequencing of the different sessions are outlined in Figure 2. Importantly, the sessions will be scheduled so that the weekly amount of exercise is progressively increased across the intervention period, both in intensity and duration [54]. The preferred exercise modality is inclined treadmill walking or running. The exercise prescription is individually tailored to each participant based on their CPET result.

In Figure 2, the intensity of each session is depicted by the colored bars as a percentage of the mean peak heart rate (HR_peak) for the session. “Black sessions” are performed at 65% of HR_peak for 25-40 minutes (n=13), “light blue sessions” are performed at 75% of HR_peak for 30 minutes (n=17), and “green sessions” are performed at 83.5% of HR_peak for 30 minutes (n=2). “Dark blue sessions” are performed as three to five 4-minute intervals at 93.5% of HR_peak with 3 minutes active rest (brisk walking) between intervals (n=16), and “purple sessions” are performed as two to four 8-minute intervals at 88% of HR_peak with 4 minutes active rest (brisk walking) between intervals (n=8). Orange bars represent sessions where the CPET exercise protocol is repeated and are conducted every fourth week (n=4). The treadmill speed and grade at voluntary exhaustion at the CPET protocol sessions will be recorded and used to monitor and report training progression throughout the intervention.

All exercise sessions will be supervised by an instructor at the participant’s local gym. The instructors make sure that the planned exercise sessions are performed and adjust the sessions if necessary. They will also register any deviation from the exercise prescription and report the reason for any adjustment following metrics suggested by Nilsen et al [55]. Adverse events will be reported to the study staff. To increase exercise adherence and educate the instructors, the instructors will be encouraged to undergo a series of web-based seminars. They will be introduced to the rationale for the study, behavior change principles, and how to identify facilitators and barriers to exercise.

BCS randomized to the control group will be encouraged to maintain their current activity level at the time of randomization.

The sample size calculation was based on the primary outcome VO_2peak, using a mean change of 3.6 (SD 7.2) mL/kg/minute, from a comparable intervention by Adams et al [23]. With a significance level of 5% and a power of 90% (to compensate for using published results from a single study in our sample size calculation), 63 BCS are needed in each group. To allow for a dropout rate of 7 participants (10%), a total of 70 BCS are included in each group. The same number of participants are included in the reference group. The primary and secondary outcomes are analyzed by generalized linear mixed models. Baseline outcomes in women with and without previous cancer are compared by a 2-sample t test.